Journal
ONCOTARGET
Volume 8, Issue 24, Pages 39185-39197Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.16642
Keywords
multiple myeloma; PDK1; mTOR; PTEN
Categories
Funding
- National Natural Science Foundation of China [81670178, 81370645, 81302036]
- National Key Research and Development Program of China [2016YFC090150X]
- Research Project for Practice Development of National TCM Clinical Research Bases [JDZX2015113]
- Funds of Health and Family Planning Commission of Zhejiang Province [2014RCA006, 2016KYB095]
- Department of Education of Zhejiang Province [Y201636714]
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A deeper understanding of the complex pathogenesis of multiple myeloma (MM) continues to lead to novel therapeutic approaches. Prior studies suggest that 3-phosphoinositide-dependent kinase 1 (PDK1) is expressed and active, acting as a crucial regulator of molecules that are essential for myelomagenesis. In the present study, we show that GSK2334470 (GSK-470), a novel and highly specific inhibitor of PDK1, induces potent cytotoxicity in MM cell lines including Dexamethasoneresistant cell line, but not in human normal cells. Insulin-like growth factor-1 could not rescue GSK-470-induced cell death. Moreover, GSK-470 down-modulates phosphor-PDK1, thereby inhibiting downstream phosphor-AKT at Thr308 and mTOR complex 1 (mTORC1) activity. However, GSK-470 could not affect mTORC2 activity and phosphor-AKT at Ser473. RPMI 8226 and OPM-2 cells with low expression of PTEN show relative resistant to GSK-470. Knockout of PTEN by shRNA resulted in a partial reversion of GSK-470-mediated growth inhibition, whereas overexpression of PTEN enhanced myeloma cell sensitivity to GSK-470, suggesting that the sensitivity to GSK-470 is correlated with PTEN expression statue in MM cells. Combining PP242, a dual mTORC1/C2 inhibitor, with GSK-470, had greater antimyeloma activity than either one alone in vitro and in MM xenograft model established in immunodeficient mice. In particular, this combination was able to result in a complete inhibition of mTORC1/C2 and full activity of AKT. Together, these findings raise the possibility that combining PDK1 antagonist GSK-470 with mTORC1/C2 inhibitors may represent a novel strategy against MM including drug-resistant myeloma, regardless of PTEN expression status.
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